Introduction
Baricitinib is a selective and reversible Janus kinase (JAK) 1 and JAK2 inhibitor with anti-inflammatory and immunomodulatory effects. By blocking JAK1/2 signaling, it suppresses the activity of pro-inflammatory cytokines involved in autoimmune diseases such as rheumatoid arthritis, helping to reduce inflammation, prevent joint damage, and improve symptoms. Preclinical studies have demonstrated that baricitinib not only reduces inflammation but also preserves cartilage and bone without significant suppression of humoral immunity or adverse hematologic effects. It has also been investigated for use in COVID-19 due to its ability to modulate excessive inflammatory responses.
Uses
Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist.
Indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs as monotherapy or in combination with methotrexate.
Associated Conditions
Mechanism of Action
JAK enzymes are part of the family of tyrosine kinases that constitutively bind to the intracellular domains of cytokine receptors and promote the signalling cascades of cytokines and growth factors involved in haematopoiesis, inflammation and immune function that are also implicated in the pathogenesis of rheumatoid arthritis . Circulating proinflammatory cytokines bind to these cell surface receptors. Upon binding of extracellular cytokines and growth factors, JAKs are phosphorylated and activate signal transducers and activators of transcription (STATs). Through the signalling cascades, inflammatory cytokine and chemokine transcription is induced to form inflammatory mediators including IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ and GM-CSF .
Baricitinib selectively and reversibly inhibits JAK1 and JAK2 to modulates their signalling pathways, thereby reducing the phosphorylation and activation of STATs . In isolated enzyme assays, baricitinib also exhibited an inhibitory effect on other types of JAK enzymes,Tyrosine Kinase 2 and JAK3, at higher concentrations needed for JAK1/2 inhibition.
Absorption
Baricitinib diaplays a dose-proportional increase in systemic exposure in the therapeutic dose range with linear pharmacokinetics. When orally administered, baricitinb is rapidly absorbed with an oral bioavailability of approximately 79 % (CV = 3.94 %). It has a median time to reach peak plasma concentration (Tmax) of 1hour (range: 0.5-3hours). Food consumption affects the exposure by decreasing it by up to 14 %, and decreasing the peak plasma concentration (Cmax) by up to 18 % and Tmax by 0.5 hours .
Volume of Distribution
Mean volume of distribution following intravenous infusion administration is 76 L .
Protein Binding
Baricitinib is approximately 50 % bound to plasma proteins .
Route of Elimination
In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and feces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in feces) constituting approximately 5 % and 1 % of the dose, respectively .
Half Life
Mean half-life in patients with rheumatoid arthritis is approximately 12.5 hrs (CV = 27.4 %) .
Clearance
Mean apparent clearance (CL/F) in patients with rheumatoid arthritis is approximately 9.42 L/hr (CV = 34.3 %) .
Toxicity
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Although unknown clinical relevance, bariticinib has shown to decrease the counts in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissues of the immune system in mice, rats and dogs. Opportunistic infections related to demodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure. At doses approximately 6-36 times the indicated doses in humans, decreases in red blood cells was observed in mice, rats and dogs.
In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively). Baricitinib decreased fertility and conception indices in a combined male/female rat fertility study. Decreased overall maing performance was likely due to altered reproductive functions of female rats, as there were no detectable changes on spermatogenesis or semen/sperm endpoints in male rats. In female rats, there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos. In a dog pre- and postnatal development study, there were decreased pup weights at exposure 4 times the human exposure and decreased postnatal survival following exposure 21 times the human exposure. Baricitinib was detected in the milk of lactating rats {FDA Label].
Clinical relevance in humans is not yet established. All the adverse reactions associated with baricitinib are expected to occur dose-dependently.
Food Interactions
- Take at the same time every day.
- Take with or without food.
Dosage
Pediatric Use: The safety and effectiveness of Baricitinib in pediatric patients have not been established.
Geriatric Use: Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.
Hepatic Impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment.
Renal impairment: Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/I .73 m2.
